title: Functional and structural evaluation of lamotrigine treatment in rat models of acute and chronic ocular hypertension.
abstract: Voltage gated sodium channels (Nav), are proposed mediators of neuronal damage in ischemic and excitotoxicity disease models. We evaluated the neuroprotective effects of lamotrigine, a Nav blocker, in the acute and chronic rat ocular hypertension models. Additionally, expression of the main Nav subtypes in the optic nerve (ON) was assessed to test whether their upregulation plays a role in the pathogenesis of ocular hypertension induced optic neuropathy. Unilateral intraocular pressure (IOP) elevation was induced for 60 min (80 mmHg) and 14-21 days (670-859 mmHg*day) in the acute and chronic models, respectively. Lamotrigine was administered at dosages of 10 mg/kg twice daily and 12.5 mg/kg once daily in the acute (n = 9) and chronic (n = 11) trials, respectively. Treatment began 2 days prior to IOP elevation until sacrifice. Outer and inner retinal function was evaluated with dark- and light-adapted flash electroretinography and pattern electroretinography, respectively, 6 and 14 days post acute IOP elevation and 13, 28 and 48 days post chronic IOP elevation. Retinal ganglion cell and axon densities and inflammatory reaction were evaluated through Fluorogold, Bielschowsky's silver impregnation and ED1 labeling respectively. Immunohistochemistry for Nav1.1, 1.2 and 1.6 was performed in ONs of untreated rats 7 and 15 days post IOP elevation in the acute model and after 7, 28 and 50 days in the chronic model. In the acute model, no differences were found in the a-wave amplitudes between lamotrigine-treated and vehicle-treated rats. B-wave amplitudes decreased by 40-66% in both treatment groups 6 days post IOP elevation, with no significant difference between groups (p = 0.38). However, a partial recovery of b-wave amplitudes was found in lamotrigine-treated rats between day 6 and day 14 post procedure (p < 0.05). No differences were found in any other parameter tested in this model. Similarly, lamotrigine treatment did not result in any beneficial effect in structural parameters of the chronic model. Functional evaluation of this model was inconclusive due to super-normal values in the hypertensive eyes. Up-regulation of Nav1.1 and 1.2 expression was found in both models, beginning by day 7; an increase of the former continued in a time-dependent manner in the chronic model. Nav1.6 labeling was inconclusive. In conclusion we found lamotrigine treatment to be mostly ineffective in both acute and chronic ocular hypertension models.
authors.affiliation: Koret School of Veterinary Medicine, The R.H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Sandalon
authors.forename: Birte
authors.initials: B
authors.lastname: Könnecke
authors.forename: Hani
authors.initials: H
authors.lastname: Levkovitch-Verbin
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.forename: Katharina
authors.initials: K
authors.lastname: Hein
authors.forename: Muriel B
authors.initials: MB
authors.lastname: Sättler
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Ron
authors.initials: R
authors.lastname: Ofri
mesh_terms: D000208:Acute Disease; D000287:Administration, Topical; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004596:Electroretinography; D007429:Intraocular Pressure / Q000187:drug effects*; D000077213:Lamotrigine; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009883:Ophthalmic Solutions; D009900:Optic Nerve / Q000473:pathology; D009901:Optic Nerve Diseases / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D014065:Tonometry, Ocular; D014227:Triazines / Q000627:therapeutic use*; D015854:Up-Regulation; D061567:Voltage-Gated Sodium Channel Blockers / Q000627:therapeutic use*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D009883:Ophthalmic Solutions; D014227:Triazines; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D000077213:Lamotrigine
keywords: ERG; FERG; IHC; IOP; LTG; Na(v); ON; PERG; RGC; electroretinogram; electroretinography; full field ERG; glaucoma; immunohistochemistry; intraocular pressure; lamotrigine; neuroprotection; optic nerve; pattern ERG; retinal ganglion cell; retinal ganglion cells; sodium channels; voltage gated sodium channel